The normal structure of the oral mucosa and skin is maintained by continuous cell proliferation of the epithelium. There is evidence that only a small fraction of the dividing epithelial cells, stem cells, have the ability to proliferate indefinitely to provide the cells necessary for tissue renewal throughout the life span. Other dividing cells are capable of a series divisions which amplify the differentiated tissue mass but are committed to differentiation and death. Thus, after epithelial loss, for example, through wounding or radiation, only the stem cells are capable of restoring stable structure. As the only cells permanently resident within the epithelium, stem cells most probably form the target cells for the initiation and promotion of carcinogenesis. Most of the information about stem cell patterns of proliferation has been derived from work with haemopoietic tissues but the structural organization of epithelia appears to offer some investigative advantages. Previous work has indicated the existence of slowly-cycling basal keratinocytes with patterns of behavior (both in vivo and in vitro) suggestive of stem cell function. To investigate further the behavior of epithelial stem cells, the proposed research will use cell labeling, autoradiography, tissue culture, computer simulation and other techniques to examine the pattern of amplification division in epithelia, the response of stem cells to radiation and other phase-specific cytoxic agents, their response to promotors of carcinogenesis and their role in tissue regeneration.